The present invention relates to new linear or cyclic ureas, and to pharmaceutical composition containing them.
The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known to be a pathogenic and/or aggravating mechanism. Such pathologies are: atherosclerosis, the existence of vascular risk factors (dyslipidaemia, diabetes, systemic arterial hypertension), the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The said compounds are also useful in the treatment of patients undergoing heart transplantation or vascular repermeabilisation such as a bypass, thrombolysis or arterial dilatation with or without a stent.
A reduction in the vascular availability of nitrogen monoxide (NO) constitutes the major mechanism of endothelial dysfunction observed in the diseases and pathological conditions mentioned above and explains its pathogenic role (Cardiovasc. Res., 1999, 43, 572; Coronary. Art. Dis. 1999, 10, 277; Coronary. Art. Dis., 1999, 10, 301; Coronary. Art. Dis., 1999, 10, 287; Coronary. Art. Dis., 1999, 10, 295).
In the said pathological conditions, the endothelial dysfunction may in fact result from two main mechanisms: 1) inadequate production of NO associated with inhibition of endothelial NO synthase by endogenous inhibitors such as ADMA (asymmetric dimethylarginine), the plasma concentration of which increases in patients exhibiting cardiovascular risk factors (Cardiovasc. Res., 1999, 43, 542; Hypertension, 1997, 29, 242; Circulation, 1997, 95, 2068), 2) inactivation of the NO by the superoxide anion (O2xe2x88x92), the production of which is increased in pathological conditions (Cardiovasc. Res., 1999, 43, 562; Eur. J Biochem. 1997, 245, 541; J. Clin. Invest., 1993, 91 2546).
Under normal conditions, NO produces major effects such as: 1) regulation of arterial vasomotricity by means of its vasodilator effect (N Engl. J Med., 1993, 329, 2002; Nature, 1980, 288, 373), 2) limitation of platelet adhesion and aggregation (Trends Pharmacol. Sci., 1991, 12, 87), 3) control of the adhesion of leukocytes and monocytes to endothelial cells (Proc. Natl Acad. Sci. USA, 1991, 88, 4651), 4) inhibition of the proliferation of vascular smooth muscle cells (Cardiovasc. Res., 1999, 43, 580, Circulation, 1993, 87 V51), which explains why the deficiency of NO in the arterial wall is favourable to pathological phenomena such as vasoconstriction, thrombosis, lipid accumulation and proliferation of vascular smooth muscle cells.
In vitro experiments have enabled it to be shown that the compounds of the present invention are capable of limiting the endothelial dysfunction and reduced vascular availability of NO that are caused by tests involving the two physiopathological mechanisms already mentioned: inhibition of endothelial NO synthase and oxidative stress due to production of O2xe2x88x92.
Besides the fact that they are new, the compounds of the present invention, by virtue of their specific pharmacological activity, which is capable of limiting the development of endothelial dysfunction, are useful in preventing the development, extension and complications of atherosclerotic lesions, especially in patients exhibiting a vascular risk factor (dyslipidaemia, diabetes, arterial hypertension), and in treating the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The compounds are also used for preventing vascular complications (spasm, thrombosis, restenosis, accelerated atherosclerosis) in patients undergoing a bypass, vascular dilatation with or without a stent or other forms of vascular repermeabilisation and also heart transplantation.
Compounds of similar structure have been described in the literature, that being the case, more especially, for Patent Application WO 94/13659, which claims compounds containing especially a cyclic urea structure, those compounds being useful in the treatment of diseases of the central nervous system such as depression or psychosis. Similarly, Patent Specification FR 2 338 940 describes compounds containing especially a 1-{1-[2-hydroxy-3-(aryloxy)-propyl]-4-piperidyl}-3-aryl-imidazolidin-2-one structure and claims them for their usefulness in the treatment of vascular hypertension. Finally, Patent Specification EP 0 526 342 describes new (isoquinolin-5-yl)sulphonamides, which are useful in the treatment of myocardial ischaemia.
The compounds of the present invention are clearly distinguished from that prior art, both in their particular chemical structure and in their specific pharmacological activity of endothelial protection.